Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels

Bartolomé, Fernando Benito; Wu, Huey-Dong; Burchell, Victoria; Preza, Elisavet; Wray, Selina; Mahoney, Colin; Fox, Nick C.; Calvo, Andrea; Canosa, Antonio; Moglia, Cristina; Mandrioli, Jessica; Chiò, Adriano; Orrell, Richard W.; Houlden, Henry; Hardy, John; Abramov, Andrey Y.; Plun‐Favreau, Hélène

doi:10.1016/j.neuron.2013.02.028

Cited by 133 publications

(119 citation statements)

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“…The pathology of VCP-associated degenerative diseases features ubiquitin-positive inclusions. Although some of the pathogenic VCP mutations have been shown to affect the ATPase activities (11, 12) or mitochondrial function (13,14), the effects of these mutations in protein homeostasis, especially in the cellular stress response associated with the development of degenerative diseases, are unclear. As weakened cellular stress response contribute to aging and the development of neurodegenerative diseases (15-17), it will be of great interest to determine whether the pathogenic mutations in VCP also affect cellular stress response.…”

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confidence: 99%

Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response

Wang

Qin

et al. 2016

Journal of Biological Chemistry

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Valosin-containing protein/p97(VCP) is a hexameric ATPase vital to protein degradation during endoplasmic reticulum stress. It regulates diverse cellular functions including autophagy, chromatin remodeling, and DNA repair. In addition, mutations in VCP cause inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD), as well as amyotrophic lateral sclerosis. Nevertheless, how the VCP activities were regulated and how the pathogenic mutations affect the function of VCP during stress are not unclear. Here we show that the small ubiquitin-like modifier (SUMO)-ylation of VCP is a normal stress response inhibited by the disease-causing mutations in the N-domain. Under oxidative and endoplasmic reticulum stress conditions, the SUMOylation of VCP facilitates the distribution of VCP to stress granules and nucleus, and promotes the VCP hexamer assembly. In contrast, pathogenic mutations in the VCP N-domain lead to reduced SUMOylation and weakened VCP hexamer formation upon stress. Defective SUMOylation of VCP also causes altered co-factor binding and attenuated endoplasmic reticulum-associated protein degradation. Furthermore, SUMO-defective VCP fails to protect against stress-induced toxicity in Drosophila. Therefore, our results have revealed SUMOylation as a molecular signaling switch to regulate the distribution and functions of VCP during stress response, and suggest that deficiency in VCP SUMOylation caused by pathogenic mutations will render cells vulnerable to stress insults.Valosin-containing protein (VCP/p97, cdc48, 2 is a highly conserved member of AAA (ATPase associated with diverse cellular activities) family proteins. It is mainly composed of N-domain and two ATPase domains. By forming a homohexamer and binding various co-factors via the N-domain, VCP helps to remodel, unfold, or degrade protein substrates using the energy derived from ATP hydrolysis (1-3). Due to its cellular abundance and broad interaction with a number of co-factors, key substrates, and regulators of the ubiquitin proteasome system, VCP has emerged as a vital modulator of a large variety of cellular activities, including protein degradation, ER stress response, autophagy/mitophagy, endosomal trafficking, cell cycle, and DNA repair (2, 5, 6). However, the factors that regulate VCP activities are not clear.The importance of VCP is also demonstrated by its association with cancer and degenerative diseases. VCP is highly expressed in non-small cell lung carcinoma (7), and its expression is correlated with tumor progression and prognosis (8). On the other hand, mutations in VCP have been associated with degenerative diseases, including inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS) (6, 9). Most pathogenic mutations of VCP are found in the N-domain, with a few in the ATPase domains (10). The pathology of VCP-associated degenerative diseases features ubiquitin-positive inclusions. Although some of the pathogenic VCP mutation...

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confidence: 99%

Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response

Wang

Qin

et al. 2016

Journal of Biological Chemistry

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“…Moreover, our group has previously reported a complex I deficiency in a patient with FTLD [22]. Other studies have shown that alterations in the VCP gene induced mitochondrial uncoupling that has been observed in different neurodegenerative diseases [14]. However, in our cohort, no alterations have been associated with this gene.…”

Section: Discussionmentioning

confidence: 50%

“…Several mutations in nuclear genes have been associated with the different variants of FTLD, namely microtubule-associated protein tau and progranulin genes and, less frequently, valosin-containing protein (VCP), charged multivesicular body protein 2B, TAR-DNA binding protein and fused in sarcoma genes [5,13]. Mutations in the VCP gene induce mitochondrial dysfunction leading to lower ATP levels due to reduced ATP production [14]. Some studies have identified a noncoding expanded GGGGCC hexanucleotide repeat in the C9orf72 gene, linked to chromosome 9p21, that has been strongly associated with FTLD/ALS [15,16].…”

Section: Introductionmentioning

confidence: 99%

Genetic Variation of <b><i>MT-ND</i></b> Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation

et al. 2015

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Background: Frontotemporal lobar degeneration (FTLD) is the second most common early-onset dementia. Over the last few decades, a growing number of evidence suggests mitochondrial involvement in neurodegeneration, namely modifications of mitochondrial DNA (mtDNA) contributing to energy impairment. Objective: To sequence the 7 mitochondrially encoded complex I (MT-ND) genes in 70 FTLD patients and investigate mitochondrial respiratory chain (MRC) complex I activity. Methods: A sample of 70 patients was studied (39 females and 31 males; age range: 38-82 years, mean ± SD: 63 ± 11 years) with a probable diagnosis of FTLD. Total DNA was extracted from peripheral blood, and sequencing analysis of 7 MT-ND_n (1, 2, 3, 4L, 4, 5, 6) genes was performed. Variants identified were submitted to in silico study. Spectrophotometric evaluation of MRC activity in lymphocytes was performed, and results were compared with age-matched controls. Results: A total of 358 (161 different) alterations were found in 92.9% of patients. According to in silico analysis of nonsynonymous variants, only 5 variations are possibly or probably damaging. Complex I activity is significantly decreased in patients. Conclusion: To our knowledge, this is the first report of the complete sequence of the MT-ND genes in FTLD patients and correlation with MRC activity. The high number of mtDNA variations identified and a significant decrease in complex I activity suggest a possible involvement of mtDNA alterations in FTLD. Although the majority of these alterations are not primarily pathogenic, an interaction with other mutations may occur, leading to the disease, worsening its expression or influencing age of onset.

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“…Furthermore, a missense mutation in the CHCHD10 gene encoding a mitochondrial protein apparently important for mitochondrial structure and function has recently been associated with ALS and frontotemporal dementia, and muscle fibers from these patients exhibit mitochondrial abnormalities [99]. In addition to the well-characterized mitochondrial abnormalities reported in multiple mouse models of ALS involving overexpression of mutated SOD1 [97], mitochondrial abnormalities have also been reported in mutated VCP [100,101], TDP-43 [102,103] and FUS [104] models. This appears to be a very early pathological feature of transgenic ALS model mice: abnormal mitochondria are evident in mice expressing mutant SOD1 before symptom onset [102,105,106].…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Targeting Mitochondrial Metal Dyshomeostasis for the Treatment of Neurodegeneration

Liddell

2015

Neurodegener. Dis. Manag.

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Mitochondrial impairment and metal dyshomeostasis are suggested to be associated with many neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Friedreich's ataxia. Treatments aimed at restoring metal homeostasis are highly effective in models of these diseases, and clinical trials hold promise. However, in general, the effect of these treatments on mitochondrial metal homeostasis is unclear, and the contribution of mitochondrial metal dyshomeostasis to disease pathogenesis requires further investigation. This review describes the role of metals in mitochondria in health, how mitochondrial metals are disrupted in neurodegenerative diseases, and potential therapeutics aimed at restoring mitochondrial metal homeostasis and function.

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Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels

Cited by 133 publications

References 39 publications

Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response

Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response

Genetic Variation of <b><i>MT-ND</i></b> Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation

Targeting Mitochondrial Metal Dyshomeostasis for the Treatment of Neurodegeneration

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